MAGE-C1/CT7 and MAGE-C2/CT10 are frequently expressed in multiple myeloma and can be explored in combined immunotherapy for this malignancy

BackgroundThe full-length membrane protein tyrosine kinase 7 (PTK7) pseudokinase, an important component of the planar cell polarity and the Wnt canonical and non-canonical pathways, is a subject of step-wise proteolysis in cells and tissues. The proteolysis of PTK7 involves membrane type-matrix metalloproteinase (MT1-MMP), members of the Disintegrin Domain and Metalloproteinase (ADAM) family, and γ-secretase. This multi-step proteolysis results in the generation of the digest fragments of PTK7. These fragments may be either liberated into the extracellular milieu or retained on the plasma membrane or released into the cytoplasm and then transported into the nucleus.ResultsWe employed the genome-wide transcriptional and kinome array analyses to determine the role of the full-length membrane PTK7 and its proteolytic fragments in the downstream regulatory mechanisms, with an emphasis on the cell migration-related genes and proteins. Using fibrosarcoma HT1080 cells stably expressing PTK7 and its mutant and truncated species, the structure of which corresponded to the major PTK7 digest fragments, we demonstrated that the full-length membrane 1–1070 PTK7, the N-terminal 1–694 soluble ectodomain fragment, and the C-terminal 622–1070 and 726–1070 fragments differentially regulate multiple genes and signaling pathways in our highly invasive cancer cell model. Immunoblotting of the selected proteins were used to validate the results of our high throughput assays.ConclusionsOur results suggest that PTK7 levels need to be tightly controlled to enable migration and that the anti-migratory effect of the full-length membrane PTK7 is linked to the down-regulation of multiple migration-related genes and to the activation of the Akt and c-Jun pathway. In turn, the C-terminal fragments of PTK7 act predominantly via the RAS-ERK and CREB/ATF1 pathway and through the up-regulation of cadherin-11. In general, our data correlate well with the distinct functionality of the full-length receptor tyrosine kinases and their respective intracellular domain (ICD) proteolytic fragments.

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“…MAGEC1 belongs to cancer/testis (CT) antigen family. The expression of MAGEC1 is frequently elevated in a variety of cancers [32,33]. …”

Section: Resultsmentioning

confidence: 99%

Downstream signaling and genome-wide regulatory effects of PTK7 pseudokinase and its proteolytic fragments in cancer cells

Golubkov

Strongin

2014

Cell Communication and Signaling

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“…Cancer-germline gene expression is induced through promoter demethylation by DNA demethylation agents (15,20,21). MAGE-A3 and MAGE-C2 (MAGE-A3/C2) have been recognized as attractive potential targets for cancer immunotherapy (22–27). Previous studies have indicated that overexpression of MAGE-A3/C2 is associated with tumor metastasis and poor clinical outcome (28,29).…”

Section: Introductionmentioning

confidence: 99%

Expression and prognostic relevance of MAGE-A3 and MAGE-C2 in non-small cell lung cancer

et al. 2017

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Melanoma-associated antigen (MAGE)-A3 and MAGE-C2 are antigens encoded by cancer-germline genes, and have been recognized as potential prognostic biomarkers and attractive targets for immunotherapy in multiple types of cancer. The present study aimed to analyze the clinicopathological significance of MAGE-A3/C2 expression in non-small cell lung cancer (NSCLC). The association between MAGE-A3/C2 mRNA and protein expression, and the pathological characteristics and overall survival of patients with NSCLC was analyzed. In addition, the functional role of MAGE-A3 in human NSCLC cell line A549 was examined in vitro. MAGE-A3/C2 mRNA expression was identified in 73% (151/206) and 53% (109/206) of patients with NSCLC, respectively. MAGE-A3/C2 protein expression was identified in 58% (44/76) and 53% (40/76) of NSCLC cases, respectively. MAGE-A3 mRNA expression was observed to be associated with smoking history, disease stage and lymph node metastasis. However, no association was identified between MAGE-C2 mRNA expression and the clinicopathological characteristics of patients with NSCLC. MAGE-A3/C2-positive patients had a poorer survival rate compared with MAGE-A3/C2-negative patients. Multivariate analysis identified that MAGE-A3 expression may serve as an independent marker of poor prognosis in patients with NSCLC. Downregulation of MAGE-A3 mRNA expression in A549 cells resulted in lower migration and colony formation rates, and a higher amount of epithelial marker and lower amount of mesenchymal marker expression compared with the control group. These results indicate that MAGE-A3 serves a role in NSCLC cell metastasis through the induction of epithelial-mesenchymal transition. In conclusion, MAGE-A3 may serve as a diagnostic and prognostic biomarker for patients with NSCLC, due to its association with tumor progression and poor clinical outcome.

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“…Its expression correlates strongly with plasma cell proliferation index, paraprotein levels, and reduced time to relapse, rendering CT7 a significant and independent negative prognostic factor for MM [3]. Evidence suggests that CT7 may play a gatekeeper function in terms of MAGE co-expression in MM [5]. CT7 may also play central roles in anti-apoptosis, in the dysregulation of cell cycle control and tumor progression, and in the development of chemotherapy resistance [3, 4, 6, 7].…”

Section: Introductionmentioning

confidence: 99%

Cancer–Testis Antigen 7 Expression and Immune Responses Following Allogeneic Stem Cell Transplantation for Multiple Myeloma

Tyler¹,

Jungbluth²,

Gnjatic³

et al. 2014

Cancer Immunology Research

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Cancer-testis antigen 7 (CT7) is the most frequently and consistently expressed MAGE antigen in multiple myeloma, exhibits tissue-restricted expression, and is an independent negative prognostic factor for multiple myeloma. We sought to characterize CT7 protein expression in the bone marrow of patients with multiple myeloma undergoing allogeneic T cell-depleted hematopoietic stem cell transplantation (alloTCD-HSCT), and to examine the significance of CT7-specific cellular immune responses. We further aimed to determine CT7-derived immunogenic epitopes and their associated allelic restrictions. CT7 protein expression in neoplastic CD138þ plasma cells was evaluated by immunohistochemistry in bone marrow biopsies from 10

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MAGE-C1/CT7 and MAGE-C2/CT10 are frequently expressed in multiple myeloma and can be explored in combined immunotherapy for this malignancy

Cited by 24 publications

References 21 publications

Downstream signaling and genome-wide regulatory effects of PTK7 pseudokinase and its proteolytic fragments in cancer cells

Downstream signaling and genome-wide regulatory effects of PTK7 pseudokinase and its proteolytic fragments in cancer cells

Expression and prognostic relevance of MAGE-A3 and MAGE-C2 in non-small cell lung cancer

Cancer–Testis Antigen 7 Expression and Immune Responses Following Allogeneic Stem Cell Transplantation for Multiple Myeloma

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